Exacerbation of type 1 diabetes in mice by bisphenol A and genistein

双酚 A 和染料木黄酮加剧小鼠 1 型糖尿病

• 批准号: 8770595
• 负责人: TAI L GUO
• 金额: $ 18.64万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770595
• 关键词: Address; Adult; Affect; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; Biological Markers; C57BL/6 Mouse; Cancer Patient; Caring; Cells; ChIP-on-chip; Childhood; Clinical; DNA; DNA Methylation; Data; Databases; Dental; Development; Disease; Dose; Economics; Elderly; Endocrine Disruptors; Enhancers; Environmental Exposure; Environmental Risk Factor; Epidemic; Epigenetic Process; Epoxy Resins; Estrogen Receptors; Estrogens; Etiology; Exposure to; Female; Food Container; Future; Gene Targeting; Genes; Genistein; Glucose; Health; Histone Acetylation; Histones; Human; Immune Tolerance; Inbred NOD Mice; Incidence; Individual; Insulin-Dependent Diabetes Mellitus; Interleukin-17; Intervention Studies; Investigation; Lead; Life; Light; Metals; Modeling; Modification; Molecular; Monozygotic Twinning; Monozygotic twins; Mus; Non obese; Organ; Pancreas; Pathogenesis; Perinatal; Perinatal Exposure; Pharmaceutical Preparations; Phytoestrogens; Pit and Fissure Sealants; Plastics; Play; Post-Translational Protein Processing; Process; Production; Quantitative Evaluations; Regulation; Regulatory T-Lymphocyte; Research Personnel; Risk; Role; Soy Foods; Spleen; Streptozocin; Suggestion; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Toy; Translating; Water; Xenobiotic Metabolism; age group; base; bisphenol A; central tolerance; chromatin immunoprecipitation; design; diabetic; fetal; genome-wide; histone modification; immunotoxicity; improved; polycarbonate plastic; postnatal; prenatal; prenatal exposure; promoter; public health relevance; research study; surveillance study; thymocyte

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an organ-specific autoimmune disease that has been showing a disturbing global increase of approximately 3% per year, predominantly in the younger age groups, over the last decades. Parallel increased exposure to endocrine disruptors (EDs) has been noted, resulting in suggestions of possible causality. Two EDs of particular significance due to their abundance are bisphenol A (BPA), used in the construction of polycarbonate plastics as well as epoxy resins found in water bottles, food containers and dental fillings, and genistein (GEN), a prevalent phytoestrogen found in soy food. Growing concerns of altered xenobiotic metabolism and synergistic interaction from combined exposure to soymilk and BPA, including in BPA-laden baby bottles, has warranted the investigation of the interactions between GEN and BPA on development-based postnatal T1D. Dysregulated T cell activity resulting from disturbed thymic central tolerance plays a key role in the T1D epidemic. Discordant T1D incidence among monozygotic twins also suggested a role for epigenetics in its manifestation. BPA and GEN both dysregulate T cell activity and cause inappropriate epigenetic modifications, supporting a possible causal role in increased T1D. The investigators hypothesize that T1D is exacerbated because thymic immune tolerance is disrupted by perinatal BPA ¿ GEN exposure in genetically susceptible female non-obese diabetic mice and streptozotocin-induced female diabetic C57BL/6 mice. The investigators believe this disruption is through inappropriate epigenetic modifications, which prime the organ for subsequent estrogen-triggering of autoimmunity during peripuberty. The above central hypothesis will be addressed in the experiments of the following two Aims: (1) Determine the exacerbation of T1D in adult female mice following perinatal exposure to GEN and BPA, and its relationship to thymic stromal microenvironment and the expression of interleukin (IL)-17 and Foxp3; and (2) Test the hypothesis that prenatal exposure to GEN and BPA causes histone post-translational modifications at the promoter/enhancer regions of T1D susceptible genes in the medullary thymic epithelial cells, and changes of DNA methylation and histone acetylation in Foxp3 and IL-17 gene loci. These aims are designed as a focused expansion of the existing BPA and GEN developmental immunotoxicity database, in a manner collectively required to understand how EDs act as "developmental origins of health and disease" compounds to increase risk of later-life T1D. Epigenetic therapy including global DNA demethylating drugs, has translated into improved care for cancer patients, and suggests potential clinical importance of proposed studies for future T1D treatment. This identification of: 1) possible gene targets that are important in increasing risks; 2) vulnerable periods in life; and 3) environmental factors which through different mechanisms may be driving the immunological processes that lead to T1D is required to make informed decisions regarding intervention studies and produce potential biomarkers for use in subsequent human surveillance studies.

描述（由申请人提供）：1型糖尿病（T1 D）是一种器官特异性自身免疫性疾病，在过去几十年中，全球每年约增加3%，主要发生在年轻年龄组。注意到内分泌干扰物（ED）暴露量的平行增加，从而提出了可能的因果关系。两种由于其丰富而特别重要的ED是双酚A（BPA），用于聚碳酸酯塑料的结构以及水瓶，食品容器和牙齿填充物中发现的环氧树脂，以及染料木素（GEN），一种在大豆食品中发现的普遍植物雌激素。对豆浆和BPA（包括含有BPA的婴儿奶瓶）组合暴露引起的异生物质代谢改变和协同作用的担忧日益增加，因此有必要调查GEN和BPA对基于发育的出生后T1 D的相互作用。由胸腺中枢耐受性紊乱引起的T细胞活性失调在T1 D流行中起关键作用。单卵双胞胎中T1 D发病率不一致也表明表观遗传学在其表现中的作用。BPA和GEN都使T细胞活性失调，并引起不适当的表观遗传修饰，支持T1 D增加的可能因果作用。研究人员假设T1 D加重是因为遗传易感的雌性非肥胖糖尿病小鼠和链脲佐菌素诱导的雌性糖尿病C57 BL/6小鼠围产期BPA？GEN暴露破坏了胸腺免疫耐受。研究人员认为，这种破坏是通过不适当的表观遗传修饰，这为随后在青春期期间雌激素触发自身免疫的器官做好了准备。以上中心假设将在以下两个目的的实验中得到解决：（1）确定围产期暴露于GEN和BPA后成年雌性小鼠T1 D的加重及其与胸腺基质微环境和白细胞介素（IL）-17和Foxp 3表达的关系;和（2）检验产前暴露于GEN和BPA导致组蛋白在启动子处的翻译后修饰的假设。胸腺髓质上皮细胞中T1 D易感基因增强子区的变化，以及Foxp 3和IL-17基因位点DNA甲基化和组蛋白乙酰化的变化。这些目标的设计是对现有BPA和GEN发育免疫毒性数据库的重点扩展，以共同需要的方式了解ED如何作为“健康和疾病的发育起源”化合物来增加晚年T1 D的风险。表观遗传学治疗，包括全球DNA去甲基化药物，已转化为改善癌症患者的护理，并建议未来T1 D治疗的拟议研究的潜在临床重要性。这种鉴定：1）可能的基因靶点， 在增加风险方面很重要; 2）生命中的脆弱时期;和3）环境因素，这些因素可能通过不同的机制驱动导致T1 D的免疫过程，需要对干预研究做出明智的决定，并产生潜在的生物标志物用于随后的人类监测研究。